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Occult nodal metastases increase the risk of cancer recurrence, demoting prognosis and quality of life of patients. While targeted drug delivery by using systemically administered nanocarriers can potentially control metastatic disease, lymph node metastases have been mainly dealt by locally injecting nanocarriers, which may not always be applicable. Herein, we demonstrated that sub-50 nm polymeric micelles incorporating platinum anticancer drugs could target lymph node metastases in a syngeneic melanoma model after systemic injection, even after removing the primary tumors, limiting the growth of the metastases. By comparing these micelles with clinically used doxorubicin-loaded liposomes (Doxil) having 80 nm, as well as a 70 nm version of the micelles, we found that the targeting efficiency of the nanocarriers against lymph node metastases was associated with their size-regulated abilities to extravasate from the blood vasculature in metastases and to penetrate within the metastatic mass. These findings indicate the potential of sub-50 nm polymeric micelles for developing effective conservative treatments against lymph node metastasis capable of reducing relapse and improving survival.
ACS Nano 2015 May 26
PMID:Systemic Targeting of Lymph Node Metastasis through the Blood Vascular System by Using Size-Controlled Nanocarriers. 2588 Apr 44

Tumor reinitiating cancer stem-like cells are responsible for cancer recurrence associated with conventional chemotherapy. We developed a doxorubicin-encapsulated polymeric nanoparticle surface-decorated with chitosan that can specifically target the CD44 receptors of these cells. This nanoparticle system was engineered to release the doxorubicin in acidic environments, which occurs when the nanoparticles are localized in the acidic tumor microenvironment and when they are internalized and localized in the cellular endosomes/lysosomes. This nanoparticle design strategy increases the cytotoxicity of the doxorubicin by six times in comparison to the use of free doxorubicin for eliminating CD44(+) cancer stem-like cells residing in 3D mammary tumor spheroids (i.e., mammospheres). We further show these nanoparticles reduced the size of tumors in an orthotopic xenograft tumor model with no evident systemic toxicity. The development of nanoparticle system to target cancer stem-like cells with low systemic toxicity provides a new treatment arsenal for improving the survival of cancer patients.
ACS Nano 2015 Jun 23
PMID:Chitosan-Decorated Doxorubicin-Encapsulated Nanoparticle Targets and Eliminates Tumor Reinitiating Cancer Stem-like Cells. 2600 86

Because of the complexity of cancer, an ideal anticancer strategy is better to target both cancer cells and the tumor microenvironment. In this study, for the first time, we demonstrated that zinc oxide nanoparticles (ZnO NPs) were able to target multiple cell types of cancer, including cancer cells, cancer stem cells (CSCs), and macrophages, and simultaneously perform several key functions, including inhibition of cancer proliferation, sensitization of drug-resistant cancer, prevention of cancer recurrence and metastasis, and resuscitation of cancer immunosurveillance. As a nanocarrier, the chemotherapy drug, doxorubicin (Dox), could be loaded to ZnO NPs and the Dox-loaded ZnO NPs (ZnO/Dox) possessed excellent physicochemical and pH-responsive drug release properties. ZnO/Dox could be effectively internalized by both drug-sensitive and multidrug resistant (MDR) cancer cells and penetrate more efficiently through three-dimensional (3D) cancer cell spheroids compared with free Dox. As a cytotoxic agent, ZnO NPs were more efficient to kill MDR cancer cells. Interestingly, neither ZnO nor Dox showed high cytotoxicity in the 3D cancer cell spheroids, whereas ZnO/Dox showed remarkable synergistic anticancer effects. More importantly, we demonstrated that ZnO NPs could effectively downregulate CD44, a key CSC surface marker, and decrease the stemness of CSCs, leading to the sensitization of the Dox treatment, inhibition of the cancer cell adhesion and migration, and prevention of the tumor (3D cancer cell spheroid) formation. As an immunomodulator, ZnO NPs could protect macrophages from the Dox-induced toxicity and boost the Dox-induced macrophage polarization toward an M1-like phenotype. The macrophage-conditioned medium could promote the cancer cell apoptosis in both cancer cell monolayers and 3D spheroids. The findings in this study indicated that ZnO NPs were a multifunctional and multitarget nanocarrier and nanomedicine that would have more profound effects on cancer treatment.
ACS Appl Mater Interfaces 2017 Nov 22
PMID:Exploration of Zinc Oxide Nanoparticles as a Multitarget and Multifunctional Anticancer Nanomedicine. 2907 44

One of the clinical challenges facing photothermal cancer therapy is health risks imposed by the photothermal nanoagents in vivo. Herein, a photothermal therapy (PTT) platform composed of a 2D material-based nanofibrous membrane as the agent to deliver thermal energy to tumors under near-infrared (NIR) light irradiation is described. The photothermal membrane, which is fabricated by an electrospinning poly(l-lactic acid) (PLLA) nanofibrous membrane loaded with bismuth selenide (Bi2Se3) nanoplates, exhibits very high photothermal conversion efficiency and long-term stability. Cell experiments and hematological analyses demonstrate that the Bi2Se3/PLLA membranes have excellent biocompatibility and low toxicity. PTT experiments performed in vivo with the Bi2Se3/PLLA membrane covering the tumor and NIR irradiation produce local hyperthermia to ablate the tumor with high efficiency. Different from the traditional systematical and local injection techniques, this membrane-based PTT platform is promising in photothermal cancer therapy, especially suitable for the treatment of multiple solid tumors or skin cancers, and long-term prevention of cancer recurrence after surgery or PTT, while eliminating the health hazards of nanoagents.
ACS Appl Mater Interfaces 2018 Jan 10
PMID:2D Material-Based Nanofibrous Membrane for Photothermal Cancer Therapy. 2923 7

Although postsurgical chemotherapy is frequently used for the treatment of breast cancer, tumor recurrence is still a frequent event. Enhancing the efficacy of chemotherapy via localized drug delivery may help to prevent breast cancer recurrence. To achieve this goal, we designed a hydrogel nanocarrier that could be injected at the tumor site by coassembly of tailor-made hexapeptide and doxorubicin. Evidently, on the basis of our findings, the sustained release of drug from the hydrogel led to a reduction in cancer recurrence, including the suppression of primary regrowth and distant metastasis. This localized chemotherapy strategy did not show any obvious side effects in vivo and represents a promising adjuvant therapeutic strategy for breast cancer recurrence.
ACS Appl Mater Interfaces 2018 Feb 28
PMID:Injectable Hexapeptide Hydrogel for Localized Chemotherapy Prevents Breast Cancer Recurrence. 2940 16

Triple-negative breast cancer (TNBC) is a malignant and refractory disease with high morbidity and mortality. The TNBC shows no response to hormonal therapy nor targeted therapy due to the lack of known targetable biomarkers. Furthermore, the TNBC also exhibits a high degree of heterogeneity that leads to cancer evolution, drug resistance, metastatic progression, and recurrence, arising from the tumor-initiating properties of cancer stem cells (CSCs). Thus, the development of radical therapeutic regimens with high efficacy and limited side effects is crucial. In this study, we designed an innovative ternary cocktail chemotherapy by using Lovastatin (L)-loaded Janus camptothecin-floxuridine conjugate (CF) nanocapsules (NCs) with ultrahigh drug loading capacity. The obtained LCF NCs were shown to be able to suppress growth of TNBC, including inhibition of growth and metastasis of CSCs, both in vitro and in tumor-bearing mice. Moreover, in animal experiments, the LCF NCs showed sustained and synchronous drug release (half-life > 300 min), 85.2% reduction in pulmonary metastases, and no cancer recurrence during one-month observation post-treatment. Thus, this innovative LCF NC design provides a simple and synergistic strategy for the development of simultaneous triple chemotherapy and could be an efficacious, safe, and amenable choice with higher therapeutic relevance and fewer toxic complications than conventional multidrug delivery systems for TNBC treatment in the future.
ACS Appl Mater Interfaces 2018 Sep 05
PMID:Loading Lovastatin into Camptothecin-Floxuridine Conjugate Nanocapsules for Enhancing Anti-metastatic Efficacy of Cocktail Chemotherapy on Triple-negative Breast Cancer. 3009 24

The combination of chemotherapeutic agents with immune stimulating agents for treating degenerative diseases, called chemoimmunotherapy, has emerged as a promising cancer treatment modality. Despite the tremendous potential, chemoimmunotherapy by the combination of drugs and immune stimulators often suffers because of the lack of controlled delivery nanostructures in the microenvironment. To this end, we show that by using pH-responsive smart nanocubes (NCs), cancer cells and tumor-associated immune cells can be precisely targeted with a chemotherapeutic agent (doxorubicin, DOX) and immune stimulating agent (plasmid ovalbumin, pOVA) for enhanced chemoimmunotherapy. The pH-responsive smart NCs protect payloads from nuclease degradation and avoid renal clearance and undergo supersensitive structural change at the extracellular tumor regions that mediate efficient release. Concurrent release of pOVA vaccines encoding tumor-specific antigen laden with polyplexes were loaded on tumor-associated immune cells and produce antigen-specific humoral immune response, whereas DOX enables effective infiltration into the cancer cells and is involved in the eradication of tumor tissues. The amount of anti-OVA IgG1 antibody produced by the intravenous administration of NC formulation was similar to that of free OVA formulation. Importantly, the combined delivery of pDNA and DOX using NCs showed significantly enhanced antitumor efficacy in B16/OVA melanoma tumor xenografts, which remarkably outperforms the monotherapy counterparts. These results suggest that pH-responsive smart NCs laden with pDNA and DOX provide a promising nanostructure for chemoimmunotherapy that simultaneously involves cancer cell killing and stimulates antigen-specific immune response to prevent cancer recurrence.
ACS Appl Mater Interfaces 2019 Apr 10
PMID:Smart pH-Responsive Nanocube-Controlled Delivery of DNA Vaccine and Chemotherapeutic Drugs for Chemoimmunotherapy. 3088 49

High locoregional recurrence of breast cancer after surgery remains a clinically appealing challenge. Local chemotherapy, especially sustainable delivery of chemotherapeutics at tumor sites by implantable hydrogels, has shown great potential to prevent cancer recurrence. However, the applications of conventional hydrogels are often limited by their intrinsic poor drug penetration into solid tumors and nonspecific drug accumulation in adjacent normal tissues. Herein, we developed a novel modular coassembly strategy to prepare a kind of pH-sensitive, tumor-specific targeting, and penetrating peptide (CRGDK)-modified doxorubicin-based prodrug nanoparticles (PDNPs), whose aqueous dispersion can undergo sol-gel transition after in vivo injection by thermo-induced self-aggregation to in situ form biodegradable hydrogel depot (PDNPs-gel), anchoring high amounts of PDNPs at tumor sites. Because of CRGDK-mediated targeting to overexpressed neuropilin-1 receptors on tumor vessels and tumor cells, PDNPs released from PDNPs-gel can effectively penetrate into tumor tissues, specifically enter tumor cells and finally realize intracellular acid-triggered drug release. In an in vivo incomplete resection of breast cancer model, a single peritumoral administration of PDNP-gel can achieve high inhibition efficacy against tumor recurrence. In addition, the administration of PDNP-gel only involves simple redispersion of PDNPs in water without any pretreatment for gelation, providing great convenience for storage, dosage, and prescription in practical use. Collectively, the reported multifunctional nanoparticles self-aggregated hydrogel system possesses great potential for efficient postsurgical prevention of tumor recurrence.
ACS Appl Mater Interfaces 2019 Jun 05
PMID:Injectable, Biodegradable, Thermosensitive Nanoparticles-Aggregated Hydrogel with Tumor-Specific Targeting, Penetration, and Release for Efficient Postsurgical Prevention of Tumor Recurrence. 3107 Mar 56

Considering the high rate of postsurgical tumor recurrence due to the possible residual cancer cells and the non-negligible toxicity of postsurgical systemic chemotherapy, we designed an injectable DNA hydrogel assembled by chemodrug-grafted DNA strands for localized chemotherapy. First, a multitude of camptothecin was successfully grafted on backbones of the phosphorothioate DNAs, which could be assembled into two types of Y-shaped building blocks and then hierarchically associated together to form drug-containing hydrogels. The injectable feature of drug-containing DNA hydrogels enables a minimally invasive approach for local drug administration. Owing to the enzymatic degradation, the hydrogel can gradually disassemble into nanosized particles, allowing its good permeation into the residual tumor tissue and efficient uptake by cells. Together with its sustained and responsive drug release behaviors, the drug-containing DNA hydrogel can significantly inhibit the regrowth of tumor cells and prevent cancer recurrence. Compared to the control groups, mice treated with our drug-containing DNA hydrogel show the lowest tumor relapse rate (1/3) and substantial slow tumor progression. Despite the long-term local embedding, negligible systemic toxicity and organ damages are observed after the treatment with our drug-grafted DNA hydrogel. With excellent antitumor efficacy and low side effects in vivo, our DNA-drug conjugate (DDC)-based hydrogel represents a promising candidate for local adjuvant therapy in cancer treatment.
ACS Appl Mater Interfaces 2020 May 13
PMID:Injectable Drug-Conjugated DNA Hydrogel for Local Chemotherapy to Prevent Tumor Recurrence. 3231 1

Cancer residues around the surgical site remain a significant cause of treatment failure with cancer recurrence. To prevent cancer recurrence and simultaneously repair surgery-caused defects, it is urgent to develop implantable biomaterials with anticancer ability and good biological activity. In this work, a functionalized implant is successfully fabricated by doping the effective anticancer element selenium (Se) into the potassium-sodium niobate piezoceramic, which realizes the wireless combination of electrotherapy and chemotherapy. Herein, we demonstrate that the Se-doped piezoelectric implant can cause mitochondrial damage by increasing intracellular reactive oxygen species levels and then trigger the caspase-3 pathway to significantly promote apoptosis of osteosarcoma cells in vitro. Meanwhile, its good biocompatibility has been verified. These results are of great importance for future deployment of wireless electro- and chemostimulation to modulate biological process around the defective tissue.
ACS Appl Mater Interfaces 2020 Aug 05
PMID:Wireless Electrochemotherapy by Selenium-Doped Piezoelectric Biomaterials to Enhance Cancer Cell Apoptosis. 3250 84


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